Utilization of the calcium channel blocker nimodipine in affective disorders is based on several empirical and theoretical rationales. The L-type calcium channel blocker verapamil has been reported effective in the treatment of acute mania but not depression, and nimodipine has a different profile of effects compared with verapamil. It is more lipid soluble and blocks cocaine-induced hyperactivity and dopamine overflow and is also a better anticonvulsant in several model systems. Positive response to nimodipine has been observed in one of five patients with rapid but not ultradian cycling disorder and this was confirmed in an on- off-on (B-A-B) design. Three patients with ultra-ultra rapid cycling (ultradian cycling) showed complete or partial responses to the double- blind administration of nimodipine. The partial responder was confirmed in the B-A-B design and a more complete response was achieved with the addition of carbamazepine. Since carbamazepine has recently been described to inhibit calcium influx through the NMDA receptor in cerebellar granule cells, these data raise the possibility that drugs with differential effects on calcium channels may be useful in refractory patients. One patient with recurrent brief depression responded dramatically to the blind institution of nimodipine, relapsed on placebo substitution, and re-responded with reinstitution of active drug (B-A-B- A); this patient continued to show improvement when verapamil was substituted for nimodipine. These data suggest the utility of further exploring the clinical profile of nimodipine in refractor affective disorders and of the potential of altered calcium metabolism in this illness.